US12552800B2ActiveUtilityA1
Compounds for diagnosis
Est. expiryMay 7, 2040(~13.8 yrs left)· nominal 20-yr term from priority
Inventors:MOLETTE JEROME
C07B 2200/05C07B 59/002A61K 51/0463A61K 51/0459A61K 51/0455C07D 487/04
45
PatentIndex Score
0
Cited by
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References
21
Claims
Abstract
The present invention relates to novel compounds of formula (I), or a detectably labelled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof, that can be employed in the imaging of alpha-synuclein aggregates and determining an amount thereof. Furthermore, the compounds can be used for diagnosing a disease, disorder or abnormality associated with an alpha-synuclein aggregates, including, but not limited to, Lewy bodies and/or Lewy neurites (such as Parkinson's disease), determining a predisposition to such a disease, disorder or abnormality, prognosing such a disease, disorder or abnormality, monitoring the evolution of the disease in a patient suffering from such a disease, disorder or abnormality, monitoring the progression of such a disease, disorder or abnormality and predicting responsiveness of a patient suffering from such a disease, disorder or abnormality to a treatment thereof.
Claims
exact text as granted — not AI-modifiedThe invention claimed is:
1 . A compound of formula (I)
or a detectably labelled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof,
wherein
is an aryl or a heteroaryl which is directionally selected from the group consisting of:
R 0 is H or C 1 -C 4 alkyl;
R 1 is —CN; or halo; or C 1 -C 4 alkyl; or C 1 -C 4 alkoxy; or —N(C 1 -C 4 alkyl) 2 ; or —NH(C 1 -C 4 alkyl); or H;
or
R 1 is —NH—C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyl, or heterocyclyl, wherein the heterocyclyl is a 4- to 6-membered non-aromatic monocyclic ring radical containing 1 or 2 heteroatoms, each of which is optionally substituted with at least one halo;
R 2 is selected from the group consisting of:
wherein
R 2a , R 2a′ are independently H, or F;
R 2b is independently F, OH, C 1 -C 4 alkyl, haloC 1 -C 4 alkyl, NH 2 , CN, or C 1 -C 4 alkoxy;
R 2c , R 2c′ are independently H, F, OH, OCH 3 , or CH 3 ;
R 2d is H, F, or OH;
R 2e is H, OH, CH 3 , or F;
Z is independently N, NH, N(C 1 -C 4 alkyl), N(haloC 1 -C 4 alkyl), O, or S;
Z 1 is independently N, NH, O, or S;
p is 0, 1 or 2;
m is 0 or 1;
as valency permits, is a combination of single and double bonds; and
* is the position of bonding.
2 . The compound according to claim 1 , having a formula (IIa), (IIb), (IIIa), (IIIb), or (IIIc)
or a detectably labelled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof.
3 . The compound according to claim 1 , wherein R 1 is —NH—C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyl, or heterocyclyl, each of which is optionally substituted with at least one halo, wherein the heterocyclyl is a 4- to 6-membered non-aromatic monocyclic ring radical containing 1 or 2 heteroatoms.
4 . A compound, which is one of the following compounds:
or a detectably labelled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof.
5 . A detectably labelled compound of formula (I)
stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein
is an aryl or a heteroaryl which is directionally selected from the group consisting of:
R 0 is H or C 1 -C 4 alkyl;
R 1 is —CN; or halo; or C 1 -C 4 alkyl; or C 1 -C 4 alkoxy: or —N(C 1 -C 4 alkyl) 2 ; or —NH(C 1 -C 4 alkyl); or H;
or
R 1 is —NH—C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyl, or heterocyclyl, which is a 4- to 6-membered non-aromatic monocyclic ring radical containing 1 or 2 heteroatoms, each of which is optionally substituted with at least one halo;
R 2 is selected from the group consisting of:
wherein
R 2a , R 2a′ are independently H, or F;
R 2b is independently F, OH, C 1 -C 4 alkyl, haloC 1 -C 4 alkyl, NH 2 , CN, or C 1 -C 4 alkoxy;
R 2c , R 2c′ are independently H, F, OH, OCH 3 , or CH 3 ;
R 2d is H, F, or OH;
R 2e is H, OH, CH 3 , or F;
Z is independently N, NH, N(C 1 -C 4 alkyl), N(haloC 1 -C 4 alkyl), O, or S;
Z 1 is independently N, NH, O, or S;
p is 0, 1 or 2;
m is 0 or 1;
as valency permits, is a combination of single and double bonds; and
* is the position of bonding,
wherein the compound is a detectably labelled compound.
6 . The detectably labelled compound of formula (I) according to claim 5 , wherein
R 1 is
or
R 1 is
wherein
F means 19 F; and
the compound of formula (I) is detectably labelled at least at one available position by 3 H (Tritium);
or
wherein the detectably labelled compound is
wherein
T means 3 H (Tritium) and
F means 19 F;
or a pharmaceutically acceptable salt, hydrate, or solvate thereof.
7 . A method of imaging of alpha-synuclein aggregates, comprising performing said imaging with the aid of the detectably labelled compound according to claim 5 , or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof.
8 . A diagnostic composition comprising the detectably labelled compound according to claim 5 , or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof, and at least one pharmaceutically acceptable excipient, carrier, diluent or adjuvant.
9 . A method selected from the group consisting of
(A) a method of imaging a disease, disorder or abnormality associated with alpha-synuclein aggregates in a subject, the method comprising the steps:
(a) administering the detectably labelled compound according to claim 6 , or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof, to the subject;
(b) allowing the compound to bind to the alpha-synuclein aggregates; and
(c) detecting the compound bound to the alpha-synuclein aggregates;
(B) a method of imaging a disease, disorder or abnormality associated with alpha-synuclein aggregates in a subject, the method comprising the steps:
(a) administering the detectably labelled compound according to claim 6 , or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof, to the subject; and
(b) imaging the brain of the subject;
(C) a method of imaging a disease, disorder or abnormality associated with alpha-synuclein aggregates in a subject according to above method (A) or (B), the method comprising the steps:
(a) administering the detectably labelled compound according to claim 6 , or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof;
(b) allowing the compound to bind to the alpha-synuclein aggregates;
(c) detecting the compound bound to the alpha-synuclein aggregates; and
(d) generating an image representative of the location and/or amount of the compound bound to the alpha-synuclein aggregates;
(D) a method of positron emission tomography (PET) imaging of alpha-synuclein aggregates in a tissue of a subject, the method comprising the steps:
(a) administering the detectably labelled compound according to claim 6 , or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof, to the subject;
(b) allowing the compound to penetrate into the tissue of the subject; and
(c) collecting a positron emission tomography (PET) image of the tissue of the subject;
wherein the tissue is tissue of the central nervous system (CNS), tissue of the eye or brain tissue;
(E) a method of detecting a neurological disease, disorder or abnormality associated with alpha-synuclein aggregates, in a subject, the method comprising the steps:
(a) administering the detectably labelled compound according to claim 6 , or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof, to the subject;
(b) allowing the compound to bind to the alpha-synuclein aggregates; and
(c) measuring the radioactive signal of the compound, which is bound to the alpha-synuclein aggregates;
(F) a method for the detection and/or quantification of alpha-synuclein aggregates in a tissue of a subject, the method comprising the steps:
(a) contacting the tissue with the detectably labelled compound according to claim 6 , or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof, to the subject;
(b) allowing the compound to bind to the alpha-synuclein aggregates; and
(c) detecting and/or quantifying the compound bound to the alpha-synuclein aggregates by positron emission tomography,
(G) a method of the diagnostic imaging of the brain of a subject, the method comprising the steps:
(a) administering the detectably labelled compound according to claim 6 , or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof, to the subject; and
(b) obtaining an image of the brain of the subject using positron emission tomography;
(H) a method of collecting data for the diagnosis of a disease, disorder or abnormality associated with alpha-synuclein aggregates, the method comprising the steps:
(a) bringing a sample or a specific body part or body area suspected to contain alpha-synuclein aggregates into contact with the detectably labelled compound according to claim 6 , or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof;
(b) allowing the compound to bind to the alpha-synuclein aggregates including;
(c) detecting the compound bound to the alpha-synuclein aggregates; and
(d) optionally correlating the presence or absence of the compound bound to the alpha-synuclein aggregates with the presence or absence of the alpha-synuclein aggregates in the sample or specific body part or body area,
(I) a method of collecting data for determining a predisposition to a disease, disorder or abnormality associated with alpha-synuclein aggregates, the method comprising the steps:
(a) bringing a sample or a specific body part or body area suspected to contain alpha-synuclein aggregates into contact with the detectably labelled compound according to claim 6 , or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof;
(b) allowing the compound to bind to the alpha-synuclein aggregates;
(c) detecting the compound bound to the alpha-synuclein aggregates; and
(d) optionally correlating the presence or absence of the compound bound to the alpha-synuclein aggregates with the presence or absence of the alpha-synuclein aggregates in the sample or specific body part or body area;
(J) a method of prognosing a disease, disorder or abnormality associated with alpha-synuclein aggregates, wherein the method comprises the steps:
(a) bringing a sample, a specific body part or body area suspected to contain alpha-synuclein aggregates into contact with the detectably labelled compound according to claim 6 , or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof;
(b) allowing the compound to bind to the alpha-synuclein aggregates;
(c) detecting the compound bound to the alpha-synuclein aggregates;
(d) optionally correlating the presence or absence of the compound bound to the alpha-synuclein aggregates with the presence or absence of the alpha-synuclein aggregates in the sample or specific body part or body area; and
(e) optionally repeating steps (a) to (c) and, if present, optional step (d) at least one time;
(K) a method of monitoring the progression of a disease, disorder or abnormality associated with alpha-synuclein aggregates in a patient, the method comprising the steps:
(a) bringing a sample, a specific body part or body area suspected to contain alpha-synuclein aggregates into contact with the detectably labelled compound according to claim 6 , or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof;
(b) allowing the compound to bind to the alpha-synuclein aggregates including;
(c) detecting the compound bound to the alpha-synuclein aggregates;
(d) optionally correlating the presence or absence of the compound bound to the alpha-synuclein aggregates with the presence or absence of the alpha-synuclein aggregates in the sample or specific body part or body area; and
(e) optionally repeating steps (a) to (c) and, if present, optional step (d) at least one time;
(L) a method of predicting responsiveness of a patient suffering from a disease, disorder or abnormality associated with alpha-synuclein aggregates to a treatment of the disease, disorder or abnormality associated with alpha-synuclein, the method comprising the steps:
(a) bringing a sample, a specific body part or body area suspected to contain alpha-synuclein aggregates into contact with the detectably labelled compound according to claim 6 , or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof;
(b) allowing the compound to bind to the alpha-synuclein aggregates;
(c) detecting the compound bound to the alpha-synuclein aggregates;
(d) optionally correlating the presence or absence of the compound bound to the alpha-synuclein aggregates with the presence or absence of the alpha-synuclein aggregates in the sample or specific body part or body area; and
(e) optionally repeating steps (a) to (c) and, if present, optional step (d) at least one time;
and (M) one of the above methods (H) to (L), wherein the step of optionally correlating the presence or absence of the compound bound to the alpha-synuclein aggregates with the presence or absence of the alpha-synuclein aggregates in the sample or specific body part or body area; comprises
determining the amount of the compound bound to the alpha-synuclein aggregates;
correlating the amount of the compound bound to the alpha-synuclein aggregates with the amount of the alpha-synuclein aggregates in the sample or specific body part or body area; and
optionally comparing the amount of the alpha-synuclein aggregates in the sample or specific body part or body area to a normal control value in a healthy control subject.
10 . A compound selected from the group consisting of
(A) a compound of formula (IV-F)
or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof,
wherein
R 3 is
R 4 is selected from the group consisting of:
R 2a , R 2a′ are independently H, or F;
R 2b is independently F, —OH, C 1 -C 4 alkyl, haloC 1 -C 4 alkyl, —NH 2 , —CN, or C 1 -C 4 alkoxy;
R 2c , R 2c′ are independently H, F, OH, OCH 3 , or CH 3 ;
R 2d is H, F, or —OH;
R 2e is H, OH, CH 3 , or F;
Z is independently N, NH, N(C 1 -C 4 alkyl), N(haloC 1 -C 4 alkyl), O, or S;
Z 1 is independently N, NH, O, or S;
p is 0, 1 or 2;
m is 0 or 1;
as valency permits, is a combination of single and double bonds; and
* is the position of bonding;
(B) a compound of formula (IV-H)
or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof,
wherein
R 5 is
R 6 is selected from the group consisting of:
wherein
R 2a , R 2a′ are independently H, X or F;
R 2b is independently X, F, —OH, C 1 -C 4 alkyl, haloC 1 -C 4 alkyl, —NH 2 , —CN, or C 1 -C 4 alkoxy, and wherein C 1 -C 4 alkyl, haloC 1 -C 4 alkyl, or C 1 -C 4 alkoxy optionally comprise one or more X;
R 2c , R 2c′ are independently X, H, F, OH, OCH 3 , or CH 3 ;
R 2d is X, H, F, or —OH;
R 2e is X, H, OH, CH 3 , or F;
Z is independently N, NH, N(C 1 -C 4 alkyl), N(haloC 1 -C 4 alkyl), O, or S;
Z 1 is independently N, NH, O, or S;
p is 0, 1 or 2;
m is 0 or 1;
as valency permits, is a combination of single and double bonds;
* is the position of bonding;
Fluoro is 19 F;
X is Bromo, Chloro, or Iodo; and
wherein R 6 comprises at least one X;
(C) a compound of formula (IV-J)
or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof,
wherein
R 7 is
R 8 is selected from the group consisting of:
wherein
R 2a , R 2a′ are independently H, or F;
R 2b is independently F, —OH, C 1 -C 4 alkyl, haloC 1 -C 4 alkyl, —NH 2 , —CN, or C 1 -C 4 alkoxy;
p is 0, 1 or 2;
R z is H, C 1 -C 4 alkyl or haloC 1 -C 4 alkyl;
as valency permits, is a combination of single and double bonds;
Fluoro is 19 F; and
* is the position of bonding.
11 . The compound according to claim 10 which is of formula (IV-F), wherein LG is Bromo, Chloro, Iodo, C 1-4 alkyl sulfonate or C 6-10 aryl sulfonate, wherein the C 6-10 aryl is optionally substituted by —CH 3 or —NO 2 .
12 . The compound according to claim 10 , which is of formula (IV-F), and which is of the following formula
or a pharmaceutically acceptable salt, hydrate, or solvate thereof,
wherein
LG is mesylate or nosylate;
or
which is of formula (IV-H), and which is of the following formula
or a pharmaceutically acceptable salt, hydrate, or solvate thereof;
or
which is of formula (IV-J), and which is of the following formula
or a pharmaceutically acceptable salt, hydrate, or solvate thereof.
13 . A method of preparing the compound according to claim 5 , comprising a method selected from the group consisting of
(A) reacting a compound of formula (IV-F)
or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof,
wherein
R 3 is
R 4 is selected from the group consisting of:
wherein
R 2a , R 2a′ are independently H, or F;
R 2b is independently F, —OH, C 1 -C 4 alkyl, haloC 1 -C 4 alkyl, —NH 2 , —CN, or C 1 -C 4 alkoxy;
R 2c , R 2c′ are independently H, F, OH, OCH 3 , or CH 3 ;
R 2d is H, F, or —OH;
R 2e is H, OH, CH 3 , or F;
Z is independently N, NH, N(C 1 -C 4 alkyl), N(haloC 1 -C 4 alkyl), O, or S;
Z 1 is independently N, NH, O, or S;
p is 0, 1 or 2;
m is 0 or 1;
as valency permits, is a combination of single and double bonds; and
* is the position of bonding
with a 18 F-fluorinating agent, so that LG is replaced by 18 F;
(B) reacting a compound of formula (IV-H)
or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof,
wherein
R 5 is
R 6 is selected from the group consisting of:
wherein
R 2a , R 2a′ are independently H, X or F;
R 2b is independently X, F, —OH, C 1 -C 4 alkyl, haloC 1 -C 4 alkyl, —NH 2 , —CN, or C 1 -C 4 alkoxy, and wherein C 1 -C 4 alkyl, haloC 1 -C 4 alkyl, or C 1 -C 4 alkoxy optionally comprise one or more X;
R 2c , R 2c′ are independently X, H, F, OH, OCH 3 , or CH 3 ;
R 2d is X, H, F, or —OH;
R 2e is X, H, OH, CH 3 , or F;
Z is independently N, NH, N(C 1 -C 4 alkyl), N(haloC 1 -C 4 alkyl), O, or S;
Z 1 is independently N, NH, O, or S;
p is 0, 1 or 2;
m is 0 or 1;
as valency permits, is a combination of single and double bonds;
* is the position of bonding;
Fluoro is 19 F;
X is Bromo, Chloro, or Iodo; and
wherein R 6 comprises at least one X,
with a 3 H radiolabeling agent;
and
(C) reacting a compound of formula (IV-J)
or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof,
wherein
R 7 is
R 8 is selected from the group consisting of:
wherein
R 2a , R 2a′ are independently H, or F;
R 2b is independently F, —OH, C 1 -C 4 alkyl, haloC 1 -C 4 alkyl, —NH 2 , —CN, or C 1 -C 4 alkoxy;
p is 0, 1 or 2;
R z is H, C 1 -C 4 alkyl or haloC 1 -C 4 alkyl;
as valency permits, is a combination of single and double bonds;
Fluoro is 19 F; and
* is the position of bonding,
with a CT 3 radiolabeling agent,
wherein T is 3 H.
14 . The method according to claim 13 , wherein the 18 F-fluorinating agent is selected from the group consisting of K 18 F, Rb 18 F, Cs 18 F, Na 18 F, Rb 18 F, Kryptofix[222]K 18 F, tetra(C 1-6 alkyl) ammonium salt of 18 F, and tetrabutylammonium [ 18 F]fluoride.
15 . A test kit for the detection and/or diagnosis of a disease, disorder or abnormality associated with alpha-synuclein aggregates, wherein the test kit comprises at least one compound of formula (I)
or a detectably labelled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof
wherein
is an aryl or a heteroaryl which is directionally selected from the group consisting of:
R 0 is H or C 1 -C 4 alkyl;
R 1 is —CN; or halo; or C 1 -C 4 alkyl; or C 1 -C 4 alkoxy; or —N(C 1 -C 4 alkyl) 2 ; or —NH(C 1 -C 4 alkyl); or H;
or
R 1 is —NH—C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyl, or heterocyclyl, which is a 4- to 6-membered non-aromatic monocyclic ring radical containing 1 or 2 heteroatoms, each of which is optionally substituted with at least one halo;
R 2 is selected from the group consisting of:
wherein
R 2a , R 2a′ are independently H, or F;
R 2b is independently F, OH, C 1 -C 4 alkyl, haloC 1 -C 4 alkyl, NH 2 , CN, or C 1 -C 4 alkoxy;
R 2c , R 2c′ are independently H, F, OH, OCH 3 , or CH 3 ;
R 2d is H, F, or OH;
R 2e is H, OH, CH 3 , or F;
Z is independently N, NH, N(C 1 -C 4 alkyl), N(haloC 1 -C 4 alkyl), O, or S;
Z 1 is independently N, NH, O, or S;
p is 0, 1 or 2;
m is 0 or 1;
as valency permits, is a combination of single and double bonds; and
* is the position of bonding.
16 . A kit for preparing a radiopharmaceutical preparation, wherein the kit comprises a sealed vial containing at least one compound as defined in claim 10 .
17 . The method according to claim 9 , wherein the disease, disorder or abnormality is Parkinson's disease, SNCA duplication carrier, Lewy Body dementia (LBD), dementia with Lewy bodies (DLB), Parkinson's disease dementia (PDD), diffuse Lewy body disease (DLBD), Alzheimer's disease, sporadic Alzheimer's disease, familial Alzheimer's disease with APP mutations, familial Alzheimer's disease with PS-1, PS-2 or other mutations, familial British dementia, Lewy body variant of Alzheimer's disease, Down syndrome, multiple system atrophy (MSA), traumatic brain injury, chronic traumatic encephalopathy, dementia puglistica, tauopathies, Creutzfeldt-Jakob disease, Huntington's disease, motor neuron disease, amyotrophic lateral sclerosis, neuroaxonal dystrophy, neurodegeneration with brain iron accumulation type 1, a prion disease, ataxia telangiectatica, Meige's syndrome, subacute sclerosing panencephalitis, Gerstmann-Straussler-Scheinker disease, inclusion-body myositis, Gaucher disease, Krabbe disease, a lysosomal storage disorder or rapid eye movement (REM) sleep behavior disorder.
18 . The compound according to claim 1 , wherein R 1 is selected from the group consisting of
19 . The detectably labelled compound of formula (I) according to claim 5 , wherein the compound is a detectably labelled by 2 H, 3 H or 18 F.
20 . The method according to claim 7 , wherein the imaging is positron emission tomography imaging of alpha-synuclein aggregates.
21 . The method according to claim 9 , wherein the disease, disorder or abnormality is Parkinson's disease, multiple system atrophy, dementia with Lewy bodies, Parkinson's disease dementia, SNCA duplication carrier or Alzheimer's disease.Cited by (0)
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